RESUMO
Strigolactones (SLs) are plant apocarotenoids with diverse roles and structures. Canonical SLs, widespread and characterized by structural variations in their tricyclic lactone (ABC-ring), are classified into two types based on C-ring configurations. The steric C-ring configuration emerges during the BC-ring closure, downstream of the biosynthetic intermediate, carlactonoic acid (CLA). Most plants produce either type of canonical SLs stereoselectively, e.g., tomato (Solanum lycopersicum) yields orobanchol with an α-oriented C-ring. The mechanisms driving SL structural diversification are partially understood, with limited insight into functional implications. Furthermore, the exact molecular mechanism for the stereoselective BC-ring closure reaction is yet to be known. We identified an enzyme, the stereoselective BC-ring-forming factor (SRF), from the dirigent protein (DIR) family, specifically the DIR-f subfamily, whose biochemical function had not been characterized, making it a key enzyme in stereoselective canonical SL biosynthesis with the α-oriented C-ring. We first confirm the precise catalytic function of the tomato cytochrome P450 SlCYP722C, previously shown to be involved in orobanchol biosynthesis [T. Wakabayashi et al., Sci. Adv. 5, eaax9067 (2019)], to convert CLA to 18-oxocarlactonoic acid. We then show that SRF catalyzes the stereoselective BC-ring closure reaction of 18-oxocarlactonoic acid, forming orobanchol. Our methodology combines experimental and computational techniques, including SRF structure prediction and conducting molecular dynamics simulations, suggesting a catalytic mechanism based on the conrotatory 4π-electrocyclic reaction for the stereoselective BC-ring formation in orobanchol. This study sheds light on the molecular basis of how plants produce SLs with specific stereochemistry in a controlled manner.
Assuntos
Lactonas , Lactonas/metabolismo , Lactonas/química , Estereoisomerismo , Solanum lycopersicum , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/metabolismoRESUMO
Pea phytoalexins (-)-maackiain and (+)-pisatin have opposite C6a/C11a configurations, but biosynthetically how this occurs is unknown. Pea dirigent-protein (DP) PsPTS2 generates 7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene (DMDIF), and stereoselectivity toward four possible 7,2'-dihydroxy-4',5'-methylenedioxyisoflavan-4-ol (DMDI) stereoisomers was investigated. Stereoisomer configurations were determined using NMR spectroscopy, electronic circular dichroism, and molecular orbital analyses. PsPTS2 efficiently converted cis-(3R,4R)-DMDI into DMDIF 20-fold faster than the trans-(3R,4S)-isomer. The 4R-configured substrate's near ß-axial OH orientation significantly enhanced its leaving group abilities in generating A-ring mono-quinone methide (QM), whereas 4S-isomer's α-equatorial-OH was a poorer leaving group. Docking simulations indicated that the 4R-configured ß-axial OH was closest to Asp51, whereas 4S-isomer's α-equatorial OH was further away. Neither cis-(3S,4S)- nor trans-(3S,4R)-DMDIs were substrates, even with the former having C3/C4 stereochemistry as in (+)-pisatin. PsPTS2 used cis-(3R,4R)-7,2'-dihydroxy-4'-methoxyisoflavan-4-ol [cis-(3R,4R)-DMI] and C3/C4 stereoisomers to give 2',7-dihydroxy-4'-methoxyisoflav-3-ene (DMIF). DP homologs may exist in licorice (Glycyrrhiza pallidiflora) and tree legume Bolusanthus speciosus, as DMIF occurs in both species. PsPTS1 utilized cis-(3R,4R)-DMDI to give (-)-maackiain 2200-fold more efficiently than with cis-(3R,4R)-DMI to give (-)-medicarpin. PsPTS1 also slowly converted trans-(3S,4R)-DMDI into (+)-maackiain, reflecting the better 4R configured OH leaving group. PsPTS2 and PsPTS1 provisionally provide the means to enable differing C6a and C11a configurations in (+)-pisatin and (-)-maackiain, via identical DP-engendered mono-QM bound intermediate generation, which PsPTS2 either re-aromatizes to give DMDIF or PsPTS1 intramolecularly cyclizes to afford (-)-maackiain. Substrate docking simulations using PsPTS2 and PsPTS1 indicate cis-(3R,4R)-DMDI binds in the anti-configuration in PsPTS2 to afford DMDIF, and the syn-configuration in PsPTS1 to give maackiain.
Assuntos
Pisum sativum , Proteínas de Plantas , Pterocarpanos , Pisum sativum/química , Pisum sativum/metabolismo , Pterocarpanos/química , Pterocarpanos/metabolismo , Estereoisomerismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Modelos Moleculares , Conformação MolecularRESUMO
Microbial epoxide hydrolases, cis-epoxysuccinate hydrolases (CESHs), have been utilized for commercial production of enantiomerically pure L(+)- and D(-)-tartaric acids for decades. However, the stereo-catalytic mechanism of CESH producing L(+)-tartaric acid (CESH[L]) remains unclear. Herein, the crystal structures of two CESH[L]s in ligand-free, product-complexed, and catalytic intermediate forms were determined. These structures revealed the unique specific binding mode for the mirror-symmetric substrate, an active catalytic triad consisting of Asp-His-Glu, and an arginine providing a proton to the oxirane oxygen to facilitate the epoxide ring-opening reaction, which has been pursued for decades. These results provide the structural basis for the rational engineering of these industrial biocatalysts.
Assuntos
Biocatálise , Epóxido Hidrolases , Hidrolases , Epóxido Hidrolases/metabolismo , Hidrolases/química , Hidrolases/genética , Hidrolases/metabolismo , Tartaratos/metabolismo , Modelos Moleculares , Estrutura Terciária de Proteína , Estrutura Quaternária de ProteínaRESUMO
Baeyer-Villiger monooxygenases belong to a family of flavin-binding proteins that catalyze the Baeyer-Villiger (BV) oxidation of ketones to produce lactones or esters, which are important intermediates in pharmaceuticals or sustainable materials. Phenylacetone monooxygenase (PAMO) from Thermobifida fusca with moderate thermostability catalyzes the oxidation of aryl ketone substrates, but is limited by high specificity and narrow substrate scope. In the present study, we applied loop optimization by loop swapping followed by focused saturation mutagenesis in order to evolve PAMO mutants capable of catalyzing the regioselective BV oxidation of cyclohexanone and cyclobutanone derivatives with formation of either normal or abnormal esters or lactones. We further modulated PAMO to increase enantioselectivity. Crystal structure studies indicate that rotation occurs in the NADP-binding domain and that the high B-factor region is predominantly distributed in the catalytic pocket residues. Computational analyses further revealed dynamic character in the catalytic pocket and reshaped hydrogen bond interaction networks, which is more favorable for substrate binding. Our study provides useful insights for studying enzyme-substrate adaptations.
Assuntos
Oxigenases de Função Mista , Engenharia de Proteínas , Thermobifida , Estereoisomerismo , Especificidade por Substrato , Oxigenases de Função Mista/metabolismo , Oxigenases de Função Mista/química , Oxigenases de Função Mista/genética , Thermobifida/enzimologia , Thermobifida/metabolismo , Oxirredução , Biocatálise , Domínio Catalítico , Modelos MolecularesRESUMO
Ene-reductase (ER) has been widely applied for asymmetrical synthesis of chiral intermediates due to its substrate promiscuity, photoexcited reactivity, and excellent property with producing two chiral centers at a time. Natural ERs often exhibit the same stereoselectivity, and they need to be engineered for opposite configuration of chiral compounds. The hydrogenation process toward activated alkenes by ERs is composed of reductive half reaction and oxidative half reaction, which are dependent upon two cofactors NAD(P)H and flavin mononucleotide. The catalytic activity of ERs will be affected by the size of the substrate, the activating strength of the electron-withdrawing groups, redox potential of cofactors, and the loop flexibility around catalytic cavity. Currently, protein engineering to ERs has been successfully employed to enhance various catalytic properties, including photoexcited asymmetric synthesis. This review summarizes the approaches to reverse the stereoselectivity and enhance catalytic activity of ERs and new applications of the engineered ERs in photobiocatalytic asymmetric synthesis, besides the discussion with the existing molecular mechanisms of mutants regarding the improved catalytic performance.
RESUMO
A convergent synthesis of the dodecasaccharide scaffold of axinelloside A was achieved through Au(I)-catalyzed [6+6] glycosylation. The initially devised [3+1+2] assembly of the nonreducing hexasaccharide fragment was low-yielding, whereas a convergent [3+3] glycosylation under Au(I) catalysis was proven feasible, allowing for a semi-gram scale preparation of the wanted hexasaccharide. The requisite 1,2-cis glycosidic bonds were forged in a highly stereoselective fashion by virtue of remote acetyl group participation, and judicious manipulation of protecting groups. The synthetic dodecasaccharide has been properly protected for the downstream elaboration toward its natural form.
Assuntos
Glicosídeos , Lipopolissacarídeos , Glicosilação , Catálise , EstereoisomerismoRESUMO
To facilitate the discovery and development of new pharmaceuticals, the demand for novel stereofunctionalised building blocks has never been greater. Whilst molecules bearing quaternary and tetrasubstituted stereogenic centres are ideally suited to explore untapped areas of chemical space, the asymmetric construction ofsterically congested carbon centres remains a longstanding challenge in organic synthesis. The enantioselective assembly of acyclic stereogenic centres is even more demanding due to the need to restrict a much wider range of geometries and conformations of the intermediates involved. In this context, the catalytic asymmetric allylicalkylation (AAA) of acyclic prochiral nucleophiles, namely enolates, has become an indispensable tool to access a range of linearα-quaternary andα-tetrasubstituted carbonyl compounds. However, unlike the AAA of cyclic enolates with a fixed enolate geometry, to achieve high levels of stereocontrol in the AAA of acyclic enolates, the stereoselectivity of enolisation must be considered. The aim of this review is to offer acomprehensivediscussion of catalytic AAA reactions of acyclic prochiral enolates and their analogues to generate congested quaternary and tetrasubstituted chiral centres using metal, non-metal and dual catalysis, with particular focus given to the control of enolate geometry and its impact on the stereochemical outcome of the reaction.
RESUMO
Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.
RESUMO
(Z)-alkenes are useful synthons but thermodynamically less stable than their (E)-isomers and typically more difficult to prepare. The synthesis of 1,4-hetero-bifunctionalized (Z)-alkenes is particularly challenging due to the inherent regio- and stereoselectivity issues. Herein we demonstrate a general, chemoselective and direct synthesis of (Z)-2-butene-1,4-diol monoesters. The protocol operates within a Pd-catalyzed decarboxylative acyloxylation regime involving vinyl ethylene carbonates (VECs) and various carboxylic acids as the reaction partners under mild and operationally attractive conditions. The newly developed process allows access to a structurally diverse pool of (Z)-2-butene-1,4-diol monoesters in good yields and with excellent regio- and stereoselectivity. Various synthetic transformations of the obtained (Z)-2-butene-1,4-diol monoesters demonstrate how these synthons are of great use to rapidly diversify the portfolio of these formal desymmetrized (Z)-alkenes.
RESUMO
The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.
Assuntos
Melatonina , Quinolinas , Ligantes , Receptores de Melatonina , Melatonina/metabolismo , Amidas , Receptor MT2 de Melatonina/metabolismo , Receptor MT1 de Melatonina/metabolismoRESUMO
A series of binuclear rare-earth metal complexes based on the ligands containing bis(phosphinophenyl)amido-PNP unit are successfully synthesized. All the ligands and the corresponding binuclear complexes are fully characterized by NMR spectra (1H, 13C, and 31P). In conjunction with [Ph3C][B(C6F5)4], all the binuclear complexes exhibited high catalytic activity and high cis-1,4-selectivity (>99%) toward the polymerization of 1,3-conjugated dienes (isoprene, ß-myrcene and ß-farnesene) with excellent livingness at room temperature or even 80 °C.
RESUMO
S-omeprazole and R-rabeprazole are important proton pump inhibitors (PPIs) used for treating peptic disorders. They can be biosynthesized from the corresponding sulfide catalyzed by Baeyer-Villiger monooxygenases (BVMOs). During the development of BVMOs for target sulfoxide preparation, stereoselectivity and overoxidation degree are important factors considered most. In the present study, LnPAMO-Mu15 designed previously and TtPAMO from Thermothelomyces thermophilus showed high (S)- and (R)-configuration stereoselectivity respectively towards thioethers. TtPAMO was found to be capable of oxidating omeprazole sulfide (OPS) and rabeprazole sulfide (RPS) into R-omeprazole and R-rabeprazole respectively. However, the overoxidation issue existed and limited the application of TtPAMO in the biosynthesis of sulfoxides. The structural mechanisms for adverse stereoselectivity between LnPAMO-Mu15 and TtPAMO towards OPS and the overoxidation of OPS by TtPAMO were revealed, based on which, TtPAMO was rationally designed focused on the flexibility of loops near catalytic sites. The variant TtPAMO-S482Y was screened out with lowest overoxidation degree towards OPS and RPS due to the decreased flexibility of catalytic center than TtPAMO. The success in this study not only proved the rationality of the overoxidation mechanism proposed in this study but also provided hints for the development of BVMOs towards thioether substrate for corresponding sulfoxide preparation.
RESUMO
Chiral epichlorohydrin (ECH) is an attractive intermediate for chiral pharmaceuticals and chemicals preparation. The asymmetric synthesis of chiral ECH using 1,3-dicholoro-2-propanol (1,3-DCP) catalyzed by a haloalcohol dehalogenase (HHDH) was considered as a feasible approach. However, the reverse ring opening reaction caused low optical purity of chiral ECH, thus severely restricts the industrial application of HHDHs. In the present study, a novel selective conformation adjustment strategy was developed with an engineered HheCPS to regulate the kinetic parameters of the forward and reverse reactions, based on site saturation mutation and molecular simulation analysis. The HheCPS mutant E85P was constructed with a markable change in the conformation of (S)-ECH in the substrate pocket and a slight impact on the interaction between 1,3-DCP and the enzyme, which resulted in the kinetic deceleration of the reverse reactions. Compared with HheCPS, the catalytic efficiency (kcat(S)-ECH/Km(S)-ECH) of the reversed reaction dropped to 0.23-fold (from 0.13 to 0.03 mM-1 s-1), while the catalytic efficiency (kcat(1,3-DCP)/Km(1,3-DCP)) of the forward reaction only reduced from 0.83 to 0.71 mM-1 s-1. With 40 mM 1,3-DCP as substrate, HheCPS E85P catalyzed the synthesis of (S)-ECH with the yield up to 55.35% and the e.e. increased from 92.54 to >99%. Our work provided an effective approach for understanding the stereoselective catalytic mechanism as well as the green manufacturing of chiral epoxides.
Assuntos
Epicloroidrina , Hidrolases , Epicloroidrina/química , Epicloroidrina/metabolismo , Hidrolases/genética , Hidrolases/metabolismo , Hidrolases/química , Cinética , Estereoisomerismo , Escherichia coli/genética , Escherichia coli/enzimologia , Engenharia de Proteínas/métodos , alfa-Cloridrina/análogos & derivadosRESUMO
Carboxylesterases (CarEs) is an important detoxification enzyme system in phase â participating in insecticides resistance. In our previous study, SlCarE054, a CarEs gene from lepidoptera class, was screened out to be upregulated in a pyrethroids and organophosphates resistant population. Its overexpression was verified in two field-collected populations of Spodoptera litura (Lepidoptera: Noctuidae) resistant to pyrethroids and organophosphates by qRT-PCR. Spatiotemporal expression results showed that SlCarE054 was highly expressed in the pupae stage and the digestive tissue midgut. To further explore its role in pyrethroids and organophosphates resistance, its metabolism activity to insecticides was determined by UPLC. Its recombinant protein showed significant metabolism activity to cyhalothrin and fenvalerate, but not to phoxim or chlorpyrifos. The metabolic activity of SlCarE054 to ß-cypermethrin showed stereoselectivity, with higher metabolic activity to θ-cypermethrin than the enantiomer α-cypermethrin. The metabolite of ß-cypermethrin was identified as 3-phenoxybenzaldehyde. Further modelling and docking analysis indicated that ß-cypermethrin, cyhalothrin and fenvalerate could bind with the catalytic triad of the 3D structure of SlCarE054. The interaction of ß-cypermethrin with SlCarE054 also showed the lowest binding energy. Our work provides evidence that SlCarE054 play roles in ß-cypermethrin resistance in S. litura.
RESUMO
Indoxacarb is a chiral insecticide that consists of two enantiomers, S-(+)-indoxacarb and R-(-)-indoxacarb, of which only S-(+)-indoxacarb has insecticidal activity. Previous enantioselective toxicology studies of indoxacarb focused mostly on simple environmental model organisms. The lack of a toxicology evaluation of indoxacarb conducted in a mammalian system could mean that the extent of the potential health risk posed by the insecticide to humans is not adequately known. In this study, we reported on a new pair of enantiomers, S-IN-RM294 and R-IN-RM294, derived from the metabolic breakdown of S-(+)-indoxacarb and R-(-)-indoxacarb, respectively, in rats. The toxicokinetics of S-(+)-indoxacarb, R-(-)-indoxacarb, S-IN-RM294, and R-IN-RM294 in rats were evaluated to provide a more comprehensive risk assessment of these molecules. The bioavailability and excretion rates of both S-(+)-indoxacarb and R-(-)-indoxacarb were relatively low, which may be due to their faster metabolism and accumulation in the tissues. In addition, there were significant differences in the metabolism and distribution between the two indoxacarb enantiomers and their metabolites in vivo. S-(+)-Indoxacarb was found to be more easily metabolized in the blood compared with R-(-)-indoxacarb, as shown by the differences in pharmacokinetic parameters between oral and intravenous administration. Analysis of their tissue distribution showed that S-(+)-indoxacarb was less likely to accumulate in most tissues. The results obtained for the two metabolites were consistent with those of the two parent compounds. S-IN-RM294 was more readily cleared from the blood and less likely to accumulate in the tissues compared with R-IN-RM294. Therefore, whether from the perspective of insecticidal activity or from the perspective of mammalian and environmental friendliness, the application of optically pure S-(+)-indoxacarb in agriculture may be a more efficient and safer strategy.
Assuntos
Disponibilidade Biológica , Inseticidas , Oxazinas , Ratos Sprague-Dawley , Toxicocinética , Animais , Masculino , Oxazinas/farmacocinética , Oxazinas/toxicidade , Oxazinas/metabolismo , Estereoisomerismo , Inseticidas/toxicidade , Inseticidas/farmacocinética , Inseticidas/química , RatosRESUMO
Short-chain dehydrogenase/reductases (SDRs) belong to the NAD(P)(H)-dependent oxidoreductase superfamily, which have various functions of catalyzing oxidation/reduction reactions and have been generally used as powerful biocatalysts in the production of pharmaceuticals. In this study, ScSDR1 and ScSDR2, two new SDRs have been identified and characterized from Stachybotrys chartarum 3.5365. Substrate scope investigation revealed that both of the enzymes possessed the ability to oxidize ß-OH to ketone specifically, and exhibited substrate promiscuity and high stereo-selectivity for efficiently catalyzing the structurally different prochiral ketones to chiral alcohols. These findings not only suggest that ScSDR1 and ScSDR2 might be potent synthetic tools in drug research and development, but also provide good examples for further engineered enzymes with higher efficiency and stereo-selectivity.
Assuntos
Redutases-Desidrogenases de Cadeia Curta , Stachybotrys , Oxirredutases , Catálise , Álcoois/químicaRESUMO
The low percentage of recyclability of the polymeric materials obtained by olefin transition metal (TM) polymerization catalysis has increased the interest in their substitution with more eco-friendly materials with reliable physical and mechanical properties. Among the variety of known biodegradable polymers, linear aliphatic polyesters produced by ring-opening polymerization (ROP) of cyclic esters occupy a prominent position. The polymer properties are highly dependent on the macromolecule microstructure, and the control of stereoselectivity is necessary for providing materials with precise and finely tuned properties. In this review, we aim to outline the main synthetic routes, the physical properties and also the applications of three commercially available biodegradable materials: Polylactic acid (PLA), Poly(Lactic-co-Glycolic Acid) (PLGA), and Poly(3-hydroxybutyrate) (P3HB), all of three easily accessible via ROP. In this framework, understanding the origin of enantioselectivity and the factors that determine it is then crucial for the development of materials with suitable thermal and mechanical properties.
Assuntos
Ésteres , Poliésteres , Polimerização , Ésteres/química , Poliésteres/química , Polímeros , Ácido 3-HidroxibutíricoRESUMO
We synthesized six new camphor-derived homochiral thioureas 1-6, from commercially available (1R)-(-)-camphorquinone. These new compounds 1-6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:ß stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:ß. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for ß glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.
RESUMO
A new series of chiral 4,5-dihydro-1H-[1,2,4]-triazoline molecules, featuring a ß-á´ -glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (8a-j) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative 8b provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the (S)-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative 8c showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.
Assuntos
Triazóis , Humanos , Cristalografia por Raios X , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Carboidratos/química , Estrutura Molecular , Estereoisomerismo , Acetilação , Relação Estrutura-Atividade , Espectroscopia de Ressonância MagnéticaRESUMO
Because internal alkenes are more challenging synthetic targets than terminal alkenes, metal-catalyzed olefin mono-transposition (i.e., positional isomerization) approaches have emerged to afford valuable E- or Z- internal alkenes from their complementary terminal alkene feedstocks. However, the applicability of these methods has been hampered by lack of generality, commercial availability of precatalysts, and scalability. Here, we report a nickel-catalyzed platform for the stereodivergent E/Z-selective synthesis of internal alkenes at room temperature. Commercial reagents enable this one-carbon transposition of terminal alkenes to valuable E- or Z-internal alkenes via a Ni-H-mediated insertion/elimination mechanism. Though the mechanistic regime is the same in both systems, the underlying pathways that lead to each of the active catalysts are distinct, with the Z-selective catalyst forming from comproportionation of an oxidative addition complex followed by oxidative addition with substrate and the E-selective catalyst forming from protonation of the metal by the trialkylphosphonium salt additive. In each case, ligand sterics and denticity control stereochemistry and prevent over-isomerization.